Controller for ultrafiltration blood circuit which prevents hypotension by monitoring osmotic pressure in blood

ABSTRACT

A device for continuously measuring osmotic pressure of blood flowing through an extracorporeal blood circuit including: a blood passage further comprising a withdrawal blood passage connectable to a blood vessel in a patient and an infusion blood passage connectable to a blood vessel in a patient; a filter further comprising a filtrate chamber, a blood chamber and a permeable membrane separating the filtrate chamber and blood chamber, wherein the blood chamber is in fluid communication with the blood passage; a pressure sensor measuring a pressure difference between the filtrate chambers and the blood chamber, and a controller receiving a pressure signal from the pressure sensor, determining an osmotic pressure across the permeable membrane of the filter, and adjusting a rate of removal of fluid from blood in the filter if the determined osmotic pressure level varies from a predetermined osmotic pressure setting.

RELATED APPLICATIONS

This application is a continuation of and claims priority to applicationSer. No. 10/648,233 (U.S. Pat. No. 7,399,289) filed Aug. 27, 2003, andapplication Ser. No. 09/721,778 (U.S. Pat. No. 6,689,083) filed Nov. 27,2000, the entirety of which applications are incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to an apparatus for the extracorporealtreatment of blood and more specifically to the automatic control fluidremoval from the blood of patients suffering from fluid overload andaverting therapy induced hypotension.

Renal replacement therapy (RRT) has evolved from the long, slowhemodialysis treatment regime of the 1960's to a diverse set of therapyoptions, the vast majority of which employ high permeability membranedevices and ultrafiltration control systems.

Biologic kidneys remove metabolic waste products, other toxins, andexcess water. They also maintain electrolyte balance and produce severalhormones for a human or other mammalian body. An artificial kidney, alsocalled a hemodialyzer or dialyzer, and attendant equipment and suppliesare designed to replace the blood-cleansing functions of the biologickidney. At the center of artificial kidney design is a semipermeablefilter membrane that allows passage of water, electrolytes, and solutetoxins to be removed from the blood. The membrane retains in the blood,the plasma proteins and other formed elements of the blood.

Over the last 15 years, the intended use of the RRT equipment the systemhas evolved into a subset of treatment alternatives that are tailored toindividual patient needs. They include ultrafiltration, hemodialysis,hemofiltration, and hemodiafiltration, all of which are delivered in arenal care environment, as well as hemoconcentration, which is typicallydelivered in open heart surgery. Renal replacement therapies may beperformed either intermittently or continuously, in the acute or chronicrenal setting, depending on the individual patient's needs.

Ultrafiltration involves the removal of excess fluid from the patient'sblood by employing a pressure gradient across a semipermeable membraneof a high permeability dialyzer. For example, removal of excess fluidoccurs in hemoconcentration at the conclusion of cardiopulmonary bypasssurgery. Hemodialysis involves the removal of toxins from the patient'sblood by employing diffusive transport through the semipermeablemembrane, and requires an electrolyte solution (dialysate) flowing onthe opposite side of the membrane to create a concentration gradient. Agoal of dialysis is the removal of waste, toxic substances, and/orexcess water from the patients' blood. Dialysis patients require removalof excess water from their blood because they lack the ability to ridtheir bodies of fluid through the normal urinary function.

One of the potential risks to health associated with RRT is hypotension,which is abnormal decrease in the patient's blood pressure. Anabnormally high or uncontrolled ultrafiltration rate may result inhypovolemic shock, hypotension, or both. If too much water is removedfrom the patient's blood, such as might occur if the ultrafiltrationrate is too high or uncontrolled, the patient could suffer hypotensionand/or go into hypovolemic shock. Accordingly, RRT treatments must becontrolled to prevent hypotension.

Alternatively, a patient may experience fluid overload in his blood, asa result of fluid infusion therapy or hyperalimentation therapy. Certainkinds of RRT machine failures may result in fluid gain rather than fluidloss. Specifically, inverse ultrafiltration may result in unintendedweight gain of a patient and is potentially hazardous. Uncontrolledinfusion of fluid by whatever mechanism into the patient could result influid overload, with the most serious acute complication being pulmonaryedema. These risks are similar in all acute and chronic renalreplacement therapies (ultrafiltration, hemodialysis, hemofiltration,hemodiafiltration, hemoconcentration). Monitoring patients to detectexcessive fluid loss is needed to avoid hypotension.

Rapid reduction in plasma or blood volume due to dialysis-associatedultrafiltration may cause a patient to exhibit one or more of thefollowing symptoms: hypovolemia-hypotension, diaphoresis, cramps,nausea, or vomiting. During dialysis, plasma volume would theoreticallyremain constant if the plasma refilling rate equaled the UF(ultrafiltration) rate. However, refilling of the plasma is often notcompleted during a dialysis session. The delay in refilling the plasmacan lead to insufficient blood volume in a patient.

There appears to be a “critical” blood volume value below which patientsbegin to have problems associated with hypovolemia (abnormally decreasedblood volume). Fluid replenishing rate is the rate at which the fluid(water and electrolytes) can be recruited from tissue into the bloodstream across permeable walls of capillaries. This way blood volume ismaintained relatively constant. Most of patients can recruit fluid atthe rate of 500 to 1000 mL/hour. When patients are ultrafiltered at afaster rate, they begin to experience symptomatic hypotension.

Hypotension is the manifestation of hypovolemia or a severe fluidmisbalance. Symptomatically, hypotension may be experienced by thepatient as light-headedness. To monitor patients for hypotension,non-invasive blood pressure monitors (NIBP) are commonly used duringRRT. When detected early, hypotension resulting from the excessive lossof fluid is easily reversed by giving the patient intravenous fluids.Following administering fluids the RRT operator can adjust theultrafiltration rate to make the RRT treatment less aggressive.

Ultrafiltration controllers were developed specifically to reduce theoccurrence of hypotension in dialysis patients. Ultrafiltrationcontrollers can be based on approximation from the known trans-membranepressure (TMP), volume based or gravity based. Roller pumps and weightscales are used in the latter to meter fluids. Ultrafiltrationcontrollers ensure the rate of fluid removal from a patient's blood isclose to the fluid removal setting that was selected by the operator.However, these controllers do not always protect the patient fromhypotension. For example, the operator may set the fluid removal ratetoo high. If the operator setting is higher than the patient's fluidreplenishing rate, the operator should reduce the rate setting when thesigns of hypotension manifest. If the excessive rate is not reduced, thepatient may still suffer from hypotension, even while the controlleroperates properly.

Attempts were made during the last two decades to develop monitors thatcould be used for feedback control of dialysis machine parameters, suchas dialysate concentration, temperature, and ultrafiltration rate andultrafiltrate volume. Blood volume feedback signals have been proposedthat are based on optical measurements of hematocrit, blood viscosityand blood conductivity. Real time control devices have been proposedthat adjust the ultrafiltration rate to maintain the blood volumeconstant, and thereby balance the fluid removal and fluid recruitmentrates. None of these proposed designs led to significantcommercialization owing to the high cost of sensors, high noise tosignal ratio or lack of economic incentive for manufacturers. Inaddition, these proposed systems required monitoring of patients byhighly trained personnel.

Controllers that protect patients from hypotension are especially neededfor patients suffering from fluid overload due to chronic congestiveheart failure (CHF). In CHF patients, fluid overload typically is notaccompanied by renal failure. In these patients mechanical soluteremoval is not required. Only fluid (plasma water) removal is needed.Ideal Renal Replacement Therapy (RRT) for these patients is SlowContinuous Ultrafiltration (SCUF) also known as “Ultrafiltration withoutDialysis”.

SCUF must be controlled to avoid inducing hypotension in the patient.Due to their poor heart condition, CHF patients are especiallyvulnerable to hypotension from excessively fast fluid removal. Theclinical treatment objective for these patients can be formulated as:Fluid removal at the maximum rate obtainable without the risk ofhypotension. This maximum rate is equivalent to fluid removal at themaximum rate at which the vascular volume can be refilled from tissue.This maximum rate for CHF patients is typically in the 100 to 1,000mL/hour range. The rate can vary with the patient's condition and isalmost impossible to predict. The rate can also change over the courseof treatment, especially if the objective of treatment is to remove 2 to10 liters of fluid.

Hypotension in CHF patients often results from a decrease of the cardiacoutput of the patient. Cardiac output is the volume of blood that isejected per minute from the heart with each heart contraction. The heartpumps approximately 4-8 L/min in the normal patient. Cardiac outputdecreases because a heart failure patient in the heart has a reducedfilling pressure. Filling pressure is the blood pressure in the rightatrium of the heart. This pressure is approximately equal to thepatient's venous pressure measured elsewhere in a great vein andcorrected for gravity. In a fluid overloaded CHF patient Central VenousPressure (CVP) is typically between 10 and 20 mmHg. If this pressuredrops by 5 to 10 mmHg, the patient is likely to become hypotensivewithin minutes.

The danger of hypotension in dialysis has been recognized. U.S. Pat. No.5,346,472 describes a control system to prevent hypotension thatautomatically adjusts the sodium concentration added to the dialysate byinfusing a hypertonic or isotonic saline solution in response tooperator input or patient's request based on symptoms. European patentEU 0311709 to Levin and Zasuwa describes automatic ultrafiltrationfeedback based on arterial blood pressure and heart rate. U.S. Pat. No.4,710,164 describes an automatic ultrafiltration feedback device basedon arterial blood pressure and heart rate. U.S. Pat. No. 4,466,804describes an extracorporeal circulation system with a blood oxygenatorthat manipulates the withdrawal of blood to maintain CVP constant. U.S.Pat. No. 5,938,938 describes an automatic dialysis machine that controlsultrafiltration rate based on weight loss or the calculated blood volumechange.

Other devices have been proposed that use arterial pressure as afeedback to the ultrafiltration controller to avoid hypotension.Automatic Non-Invasive Blood Pressure (NIBP) monitor feedback was usedas a control system input. NIBP measures systolic and diastolic arterialblood pressure by periodically inflating a blood pressure cuff aroundthe patient's arm or leg. Acoustic or oscillatory methods detect thepressure level at which blood vessels collapse. This level approximatessystemic arterial blood pressure. Closed loop dialysis or fluid removaldevices designed around this principle have several inherentdeficiencies, including:

a) NIBP is inaccurate. Errors of up to 20 mmHg can be expected in thesystem. To avoid system oscillations and false alarms, the feedbackwould have to be slow and heavily filtered.

b) NIBP is not continuous, but is rather based on periodic pressuremeasurements. If the blood pressure cuff were inflated more frequently,less than every 15 minutes a patient would experience significantdiscomfort. Also, blood vessels change their elasticity from thefrequent compressions of the blood cuff. This change in elasticity canadd to the inaccuracy of cuff pressure measurements.

c) The arterial pressure in CHF patient does not drop immediatelyfollowing the reduction of cardiac output. It may take considerable timefor a CHF patient to exhaust their cardiac reserve. By that time, thehypotension would have already occurred and its reversal would requiremedical intervention. Accordingly, hypotension may occur before NIBPdetects it.

d) In a CHF patient, arterial blood pressure is maintained by the bodyto protect the brain. Neurohormonal signals are sent in response tobaroreceptors that cause vasoconstriction of blood vessels to legs,intestine and kidneys. By sacrificing other body organs, arterial bloodpressure to the brain can be kept constant at the expense of reducedblood flow to organs while the cardiac output is reduced dramatically.Altogether, hypotension in a CHF patient can create a dangeroussituation when the arterial blood pressure is apparently normal, whilethe overall condition of the patient is worsening. By the time the NIBPmeasurement has detected hypotension, serious medical intervention maybe needed.

It is desired to have a feedback based control system that willcontinuously and automatically manipulate the ultrafiltration rate toachieve optimal ultrafiltration. In such a system, fluid is removedrapidly and without the risk of hypotension.

SUMMARY OF INVENTION

A method and system has been developed for removing fluid from a fluidoverloaded patient at a maximum safe rate that does not require humanmonitoring and interaction. The system uses an osmostic pressure in ablood filter as being indicative of conditions that cause hypotension.By monitoring osmotic pressure, the system to detect the onset ofhypotension and maintains a safe level of filtration rate by reducing orperiodically turning off ultrafiltration. Using the system, hypotensionis averted before it occurs.

A feedback system for controlling an extracorporeal blood circuit hasbeen developed that:

a) Allows optimal rate of fluid removal in vulnerable patients byautomatically measuring and monitoring various selected physiologicalparameters, in particularly, blood pressure and osmotic pressure.

b) Prevents episodes of hypotension so that treatment could be conductedunder minimal supervision.

c) Uses robust and inexpensive measurement system.

BRIEF DESCRIPTION OF THE DRAWINGS

The attached drawings and associated written description disclose anexemplary embodiment of the present invention:

FIG. 1 shows a high level schematic diagram of an ultrafiltrationsystem.

FIG. 2 illustrates relationship between hydrostatic and osmotic pressureforces.

FIG. 3 shows osmotic and hydrostatic pressures across the hemofilterfilter membrane with pumps running.

FIG. 4 shows osmotic and hydrostatic pressures across the filtermembrane with pumps stopped.

FIG. 5 shows relationship between blood hematocrit and osmotic pressureacross filter membrane established in the lab.

FIG. 6 shows theoretical and experimental correlation between bloodprotein concentration and osmotic pressure.

FIG. 7 illustrates a method of controlling ultrafiltration byestablishing a predetermined deviation of osmotic pressure from baselinevalue.

FIG. 8 shows time course of stabilization of osmotic pressure afterpumps are stopped using animal blood.

FIG. 9 illustrates design of the controller for ultrafiltrationapparatus.

FIG. 10 shows an embodiment of the invention where osmotic pressuremeasurement is separate from blood filter.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1 shows a high level schematic diagram of an ultrafiltrationsystem, such as is disclosed in commonly-owned U.S. Pat. No. 6,887,214,entitled “Blood Pump Having A Disposable Blood Passage Cartridge WithIntegrated Pressure Sensor”, and U.S. Pat. No. 6,585,675, entitled“Method And Apparatus For Blood Withdrawal And Infusion Using A PressureController” and filed Nov. 2, 2000, both of which applications areincorporated by reference in their entirety.

Blood is withdrawn from the vein 103 of a human or other mammalianpatient using a withdrawal needle 105. The blood flows from the needleinto a withdrawal bloodline 106 that is equipped with an in-linepressure sensor 107. The sensor transmits a signal indicative of theblood pressure in the withdrawal line to a computer controller 110. Thewithdrawal line loops through a blood pump 108. The pump creates asuction (negative) pressure in the withdrawal line that draws blood fromthe vein and into the line.

The pump also forces blood through a filter 111 that removes excessfluid from the blood. The filter includes a blood passage coupledbetween a blood inlet and outlet to the filter, a filtering membraneforming a portion of the walls of the passage, and a filtered fluidoutlet section on a opposite side of the membrane from the bloodpassage. The membrane is pervious to fluids, but not to blood plasma andother solutes in the blood. The filter membrane may be an artificiallipid bilayer, a plasma membrane or a layer of cells.

Some fluids (but not all) in the blood flowing through the blood passagein the filter may pass through the membrane to the outlet section andthereby be filtered from the blood. However, the plasma and solutes inthe blood cannot pass through the filter membrane and remain in theblood as it exits the filter. The filter has a blood outlet connected toa return line 113 through which flows blood to be infused back into avein 102 of the patient. The filter has a second output through whichflows separated ultrafiltrate (plasma water) that passes in a filtrateline that loops through a metering pump 114 and into a collection bag116.

The ultrafiltrate pump 114 is capable of generating a negative pressurein the filtrate line (and hence output side of the filter membrane) toassist the flux of ultrafiltrate across the membrane, which has asubstantial hydraulic resistance. The pressure level in the filtrateline and in the filtrate output section of the filter is determined bythe rotational speed of the ultrafiltrate pump 114. The rotational speedof pumps 108 and 114 is determined by a controller 110 that can be amicrocomputer. The controller receives pressure measurements from bloodline return sensor 112 and the ultrafiltrate pump sensor 109. Thecontroller is programmed to adjust the ultrafiltrate pump speed toprovide a pressure level in the filtrate line to achieve a desiredfiltration rate.

Generally, just prior to the ultrafiltration treatment, an operator,such as a nurse or medical technician, selects certain control settingson the controller for the treatment. The settings (which may be selectedby the operator or preprogrammed into the controller, or a combinationof both) may include (among other settings) a desired fluid removal ratefrom the blood. This rate may be applied by the controller to determinethe rotational speed of the ultrafiltration pump 114.

The rotational speed of the pump 114 controls the pressure (measured byultrafiltrate sensor 109) in the output section of the filter. The fluidpressure in the output section is present on one side of the filtermembrane. The fluid pressure of the blood in the blood passage ispresent on the other side of the membrane. The filtration rate isdependent on the pressure difference across the membrane of the filter.The filtration rate is controlled by the pressure in the filtrate outletsection of the filter, assuming that the blood pressure in the filterblood pressure remains constant. Accordingly, the filtration rate iscontrolled by the speed of the ultrafiltration pump 114 which determinesthe fluid pressure in the filter outlet section.

The filtrate pressure sensor 109 provides a feed back signal to thecontroller as to the fluid pressure in the outlet section of the filter.Alternative techniques to control the filtration rate are for thecontroller to adjust the blood pressure in the filter passage, or toadjust both the blood pressure in the filter and the fluid pressure inthe outlet section of the filter.

A safety feature of the controller is that it adjusts the filtrationrate to avoid hypotension of the patient. If too much fluid is removedtoo rapidly from the blood of the patient, the patient may suffer fromhypotension. The osmotic pressure across the filter membrane provides agood indicator of the blood volume and the osmotic pressure may bedetermined based on the pressure signal of the filtrate pressure sensor109 (and, if needed, based on a comparative blood pressure signal fromsensor 112 or a differential pressure sensor used between two points).

Osmotic pressure can be used to determine the protein concentration inblood and, in turn, applied to detect hypotension in a patient. Theosmotic pressure level across the filtering membrane of a blood filteris determined by difference in concentration of soluble substance (Asillustrated by FIG. 2). If two solutions (e.g., blood and a filtrateremoved from the blood) of different concentration are separated by asemi-permeable membrane which is permeable to the smaller solventmolecules but not to the larger solute molecules, then the solvent willtend to diffuse across the membrane from the less concentrated to themore concentrated solution. This process is called osmosis. Osmosis is aselective diffusion process driven by the internal energy of the solventmolecules. It is convenient to express the available energy per unitvolume in terms of “osmotic pressure”. It is customary to express thistendency toward solvent transport in pressure units relative to the puresolvent. If pure water were on both sides of the membrane, the osmoticpressure would be zero. But if normal human blood were on the right sideof the membrane and pure water on another, the osmotic pressure would beabout seven atmospheres.

Osmotic pressure may be measured by determining the amount ofhydrostatic pressure necessary to prevent fluid transfer by osmosis (703on FIG. 2). The flow of water across a membrane in response to differingconcentrations of solutes on either side—osmosis—generates a pressureacross the membrane called osmotic pressure. Osmotic pressure is thehydrostatic pressure required to stop the flow of water and isequivalent to hydrostatic pressures.

The operator enters into the controller a desired level of osmoticpressure to be present across the membrane of the filter 111. Byproperly selection the osmotic pressure level, the operator can preventexcessive reduction of blood volume in the patient and ensure safetyfrom hypotension. The controller monitors the blood and filtratepressure signals from sensors 107 and 109 (and, if present, frompressure sensors embedded in the filter and at the blood passage outlet112 of the filter). The microprocessor controller (see FIG. 9) includesalgorithms to control the ultrafiltration rate automatically based onthe changes of osmotic pressure and the settings entered by the operatorand preprogrammed into the controller.

The principles of osmosis and osmotic pressure are illustrated by theFIG. 2. The test apparatus 700 consists of two vessels separated by aselectively permeable membrane 703. In the left side of the apparatus isa solution 701 having a solute and a solvent. Water (a solvent) freelytravels through the membrane into the right side vessel 702. The poresof the membrane prevent molecules of the solute from the blood solution701 from crossing through the membrane from left to right into theoutlet section. When the system is in steady state, the blood solutionin the left container will rise so the pressure head (weight of thewater column) 703 is equal to the osmotic pressure generated by theconcentration difference.

The osmotic pressure P of a dilute solution is approximated by thefollowing equation known as Hoff's equation for ionized solutions:

$\begin{matrix}{p = {i\frac{C}{M}{RT}}} & \left( {{Equation}\mspace{20mu} 1} \right)\end{matrix}$

C=concentration of solute in g/L (grams per liter)

M=molecular weight of the solute

I=number of ions for ionized solutions

T=temperature of solution in the absolute scale or Kelvin

R=the gas constant (0.82 liter-atmosphere/degree-mole)

Osmotic pressure plays an important role in the design of a dialyzer orhemofilter. If no dialysis is performed (e.g., no dialysate is passedthrough the filter and across the separator membrane), then only thenaturally occurring blood components play role in determining theosmotic pressure gradient.

FIGS. 3 and 4 show filter 111 of an ultrafiltration device having afilter membrane 304. In the filter, the blood flows through the bloodpassage of the filter (most often hollow fibers with permeable walls).The fluid on the outside of the filter membrane is referred to asultrafiltrate or “plasma water”. In the blood flowing through the bloodpassage, blood cells constitute 25 to 45% of the total blood volume. Theblood hematocrit is the percentage of the total blood volume constitutedby blood cells. Blood cells themselves do not affect the osmoticpressure gradient across the filter membrane. Other than the cells, therest of the blood volume is plasma. Plasma is an aqueous solution ofelectrolytes such as NaCl and proteins. Water represents about 90% ofthe volume in blood plasma. Water travels freely across the hemofilterfilter membrane between the blood passage and output sectioncompartments of the filter.

Ions of NaCl and other electrolytes account for about 1% of plasma. Anumber of 9 g/L is a typical concentration of dissolved minerals inhuman blood. NaCl has molecular weight of 58.44 g/mole. From theEquation 1 it can be calculated that if the filter membrane was notpermeable to electrolytes (e.g., all the NaCl would be trapped on theblood passage side of the filter) the osmotic pressure generated by therelatively small (1%) concentration of NaCl will generate sufficienthead to support a water column roughly 74 meters high. In clinicalultrafiltration, blood filter membranes allow free convective transportof electrolytes. As a result, concentration of NaCl on both sides of themembrane is exactly the same and it does not contribute to osmoticpressure gradient.

Soluble plasma proteins are almost fully retained by the hemofiltermembrane and trapped on the blood side of the filter (e.g. insidefibers). Most significant blood protein is albumin. For simplicityfurther calculations will assume that albumin is the only proteinretained by the membrane. Albumin molecules are much larger than ions ofelectrolytes but are small enough to generate significant, and moreimportantly measurable, amount of osmotic pressure.

To illustrate the effects of a change in the concentration of protein onosmotic pressure, the osmotic pressure was determined for separation ofblood by a membrane impermeable to protein but permeable toelectrolytes. A standard hemofiltration fiber such as fibersmanufactured by Minntech of Minnesota, was used as a membrane for thefilter. Experiments were done using bovine blood with the proteinconcentration adjusted to 60 g/L, which is consistent with normalphysiologic conditions in human blood. Substitution of M=66,000 g/molefor albumin into Equation 1, gives an osmotic pressure of 17 mmHg aftermultiplying by 760 to convert pressure from atmospheres to mmHg. Theexperiments used bovine blood with an initial hematocrit of 27%, suchthat the initial volume of blood cells was 27% and the volume of plasmawith solutes accounted for the remaining 73% of the plasma volume. Outof this 73% solute volume, the protein at 60 g/L of plasma accounted for4.4% of the total volume of blood. The remaining volume was assumed tobe water and small molecules that freely permeated across the filtermembrane.

During the experiment, blood was condensed by filtering out plasma waterwith small solutes. The filter included a standard hemofiltration fibermembrane manufactured by Minntech of Minnesota. The filter membrane wasformed by 900 fibers arranged in parallel and assembled into a bundlepacked into the filter. Each fiber had internal diameter of 0.2 mm. Thistype hollow fiber filter membrane is commonly used in hemofilters,dialyzers and hemoconcentrators manufactured by many companies. Duringthe experiment, blood was gradually condensed from hematocrit of 27% tohematocrit of 40% by extracting water through the filter membrane. Thehematocrit was measured using standard lab equipment and confirmed bythe removed volume fraction measurement. Since the membrane wasimpermeable to proteins, the protein concentration in blood increased inproportion to the hematocrit. The concentration of small molecules andminerals in the blood did not change as the blood passed through thefilter.

FIGS. 3 and 4 show how the osmotic pressure can be determined in apractical apparatus (See FIG. 1). The hemofilter 111 includes a membrane304 that is permeable to water and small molecules. Blood is pumped bythe pump 108 continuously through the blood side 307 of the filter andpasses over the membrane. On an opposite side of the membrane, theultrafiltrate 308 is collected in an outlet section of the filter. Theprotein in the blood does not pass through the filter to theultrafiltrate side of the filter. The pump 114 is rotated at apredetermined rate to remove water from blood. Blood is condensed as itpasses through the filter. Typically 5 to 20% of water can be removedfrom the blood volume.

While the system is in operation, it is difficult to measure the osmoticforce. The system is in the dynamic equilibrium, and only the resultingpressures in both compartments can be measured instantaneously. Theresulting pressures on the filter membrane are the function of manycontributors such as the dynamic resistance of the filter to blood andultrafiltrate. FIG. 3 shows the dynamic relationship of the hydrostatic306 and osmotic 305 pressures across the filter membrane 304. When thesystem is operated, as shown on the FIG. 3, with both pumps pumping, twoforces act on the water molecules in the filter. Hydrostatic forces 306generated by the pumps urge water through the membrane from the bloodinto the ultrafiltrate output section. Osmotic forces 305, determinedmostly by the concentration of protein in the blood compartment 307,oppose the hydrostatic force. Dynamically measuring osmotic pressures(without the influence of hydrostatic forces) is not practical whileblood is flowing through the filter in this configuration of theapparatus.

To measure the osmotic pressure, the ultrafiltrate pump 114 is stoppedfirst to exclude the effects of filtration on the properties of blood.The blood pump 108 continues to pump blood through the filter 111, for aperiod of time at least equal to the time needed to remove the bloodtrapped in the filter and refill it with the fresh patient blood. If theblood volume of the filter is 10 mL and the blood pump flow is 60mL/min., the time for running the blood pump, after the ultrafiltratepump is stopped, will be approximately equal to 10 seconds. While theultrafiltrate pump is stopped, no fluids are being removed from theblood by the filter and the concentration of blood cells and protein inblood is the same in the blood passage of the filter as in the patient'sveins. In addition, the average pressure in both filter compartments(blood passage and ultrafiltrate output section) of the hemofilter cometo equilibrium. This average equilibrium pressure is determined by theblood flow, hydraulic resistance of the blood flow path and the osmoticpressure gradient between the two filter compartments.

Next, the blood pump 104 is stopped for a short duration of time, e.g.,approximately 10 seconds, to eliminate effects of the remaininghydrostatic forces from the filter. Since the equilibrium is establishedvia diffusion of molecules of solute across the membrane it requirescertain time to establish. This period is kept as short as possible toreduce risk of blood clotting. FIG. 4 illustrates the steady statecondition in the filter in which both pumps 114 and 108 are stopped. Thepressure difference across the membrane (between the blood passage andthe ultrafiltrate outlet sides of the membrane) as measured by thedifference in pressures determined by pressure sensors 112 and 109represents the osmotic pressure gradient across the membrane, andgravitational effects due to any height difference between the sensors.Pressure sensors 112 and 109 are shown as independent devices, but mayalso be implemented as a single differential pressure sensor used tomeasure osmotic pressure across the filter membrane. The gravitationaleffects can be determined based on the relative heights of the sensors112 and 109 and the gravitational effects, once determined, can bemathematically eliminated from the pressure measurements so that theosmotic pressure can be determined.

FIGS. 5 and 6 illustrate the results of the experiment of determiningthe relationship of blood hematocrit levels and the osmotic pressureacross a filter membrane. FIG. 5 shows that the osmotic pressuremeasured across the membrane increased in linear proportion to thehematocrit level in the blood and as the water was removed from plasma.An increase of hematocrit from 29% to 38% lead to an increase of osmoticpressure from 17 to 29 mmHg. FIG. 6 shows that the results of theexperiment are consistent with the theoretical prediction. The predictedvalues for osmotic pressure (squares) were calculated using Equation 1.Since the initial concentration of protein in blood was known, anassumption was made that the protein concentration increasedratiometrically and in inverse proportion to the removed fraction ofwater. The measured values (triangles) for osmotic pressure wereobtained using pressure transducers connected to the blood passage andultrafiltrate output section of the hemofilter. The experimental curverises steeper than the theoretical results, because Hoff's equationassumes that that osmotic pressure will increase linearly with soluteconcentration. The experimental data shows an exponential increase inosmotic pressure. For charged molecules such as proteins, the osmoticpressure also depends on pH and the ionic strength of the solution.Experimentally derived or theoretical functions may be used to predictthe concentration of protein based on measured osmotic pressure inosmotic pressure, although experimentally derived functions may bepreferable.

FIG. 7 shows an implementation of a method, described above, to controlfluid removal and prevent hypotension when using an ultrafiltrationextracorporeal circuit to remove excess fluid from a patient's blood.Osmotic pressure, plotted on the Y axis 701, is periodically measured.Dots such as 703 and 704 correspond to periodic osmotic measurementsover the time course of treatment. Since clinical filtration usuallyremoves water at slow rates 500 to 1000 mL/min, measurements can beperformed every 15 or 30 minutes. In this example, fluid removal rateexceeds the rate at which the blood volume can be replenished with thewater stored in tissue. As a result the protein concentration andosmotic pressure across the hemofilter are gradually rising between thepoint 705 corresponding to the start of treatment and the point 706 whenthe predetermined allowed level of osmotic pressure 707 is reached.Level 707 can be set by the operator at the beginning of treatment orcalculated by the machine as a function of the initial osmotic pressurelevel 702.

The initial osmotic pressure 702 level may be measured at the beginningof ultrafiltration treatment. The osmotic maximum pressure limit 707 maybe automatically established as the initial level 702 plus apredetermined delta osmotic pressure level, for example, 20% of theinitial level. When the limit level 707 is reached, the controllerautomatically stops the ultrafiltrate pump or reduces the rate at whichthe fluid is removed. The blood pump speed is not changed while theultrafiltrate pump is slowed or stopped. Between points 706 and 703, theblood volume in the blood circuit and filter is replenished frompatient's tissue. The replenishment of unfiltered blood should cause theosmotic pressure level to return to the level 702. At stage 703, theultrafiltration rate is increased. Many other control algorithms can beimplemented to control ultrafiltration rate based on the osmoticpressure across a hemofilter membrane. Existing control algorithms arewell known, and may be modified to include patient safeguards based onmonitoring osmotic pressure.

FIG. 8 illustrates the transition to steady state in the system (SeeFIGS. 2 and 3) when both pumps are stopped. The curve was obtainedexperimentally with animal blood using an apparatus similar to oneillustrated by FIG. 1. Curve 800 shows the change of pressure (verticalaxis of chart) measured by sensor 109 on the ultrafiltrate side of thefilter membrane just after the blood pump is stopped. The ultrafiltratepump was also stopped prior to the measurement. At the beginning of thetransition, before point 801, the pressure on the ultrafiltrate side ofthe filter membrane is positive and relatively high, at approximately 90mmHg. Since the ultrafiltrate pump 104 is stopped, this pressure 801 isequal to the hydrostatic pressure generated by the blood flow throughthe resistive filter circuit minus the osmotic pressure across themembrane (referenced to the atmospheric pressure). Hydrostatic pressurewill generally dominate when blood is flowing through the filter withhigh hydraulic resistance.

At the point 801, the blood pump is stopped and the hydrostatic pressureforces are eliminated. The pressure measured by the sensor 109 begins todrop and changes polarity. When the transition is complete, theultrafiltrate pressure is at −15 to −40 mmHg relative to atmosphericdepending on the concentration of protein in the patient's blood. As canbe seen from the decay curve 800 on the FIG. 8, a steady state isreached in approximately 10 seconds after the blood pump is stopped. Itis desired not to stop the flow of blood for longer than several secondsto avoid blood clots in the circuit. Delaying the filtration by stoppingthe filtrate pump does not raise a risk of clotting and, thus, theperiod during which filtration is stopped is not as time sensitive as isthe period during which the blood pump is stopped. To achieve theshortest equilibration time (e.g., 10 seconds), the circuit should haveminimal compliance and the filter should be fully primed and not trapair.

In determining osmotic pressure, the effects of gravity (altitude) onthe measurement need to be accounted for and excluded from thecalculation of osmotic pressure. The pressure generated by the weight ofthe fluid column can be expressed by Equation 2 below:

Ph=RO×G×H  (Equation 2)

Where RO is the density of fluid, G is the gravitational constant, and His the height of the sensor 109 in relation to the blood access 104 inthe patient's vein 102. Since blood has proximately the same density aswater sudden change of the position of the patient's arm by 10 cm willresult in a 7.3 mmHg shift of the Puf measured with the sensor 109.

It is assumed that the relative position of sensors 109 and 112 is knownand does not change during treatment. When the system is in steadystate, the readings of the sensors are described by Equations 3 below:

Puf=Posm+Pv+Ph

Pr=Pv+Ph  (Equations 3)

Pr=pressure measured at the machine level in the blood return line 113with the pressure sensor 112.

Puf=pressure measured at the machine level with the sensor 109 in theultrafiltrate line between the filter and the pump.

Pv=blood pressure in the patient's vein.

Ph=offset determined by the height difference between the machinemounted sensors and the patient blood return connection.

Equations 3 can be solved for osmotic pressure (Posm). Equation 4 can beused to dynamically calculate osmotic pressure across the filtermembrane, where the pressure determination is free of the influence ofthe patient's position and blood pressure.

Posm=Puf−Pr  (Equation 4)

FIG. 9 illustrates the electrical architecture of the ultrafiltrationcontroller system 900 (110 in FIG. 1), showing the various signal inputsand actuator outputs to the controller. The user-operator inputs thedesired ultrafiltrate extraction rate into the controller by pressingbuttons on a membrane interface keypad 909 on the controller. Thesesettings may include the maximum flow rate of blood through the system,maximum time for running the circuit to filter the blood, the maximumultrafiltrate rate and the maximum ultrafiltrate volume. The settingsinput by the user are stored in a memory and read and displayed by thecontroller CPU 905 (central processing unit, e.g., microprocessor ormicro-controller) on the display 910.

The controller CPU regulates the pump speeds by commanding a motorcontroller 902 to set the rotational speed of the blood pump 113 to acertain speed specified by the controller CPU. Similarly, the motorcontroller adjusts the speed of the ultrafiltrate pump 111 in responseto commands from the controller CPU and to provide a particular filtrateflow velocity specified by the controller CPU.

Feedback signals from the pressure transducer sensors 911 are convertedfrom analog voltage levels to digital signals in an A/D converter 916.The digital pressure signals are provided to the controller CPU asfeedback signals and compared to the intended pressure levels determinedby the CPU. In addition, the digital pressure signals may be displayedby the monitor CPU 914.

The motor controller 902 controls the velocity, rotational speed of theblood and filtrate pump motors 903, 904. Encoders 907, 906 mounted tothe rotational shaft of each of the motors as feedback providequadrature signals (e.g., a pair of identical cyclical digital signals,but 90° out-of-phase with one another). These signal pairs are fed to aquadrature counter within the motor controller 902 to give bothdirection and position. The direction is determined by the signal leadof the quadrature signals. The position of the motor is determined bythe accumulation of pulse edges. Actual motor velocity is computed bythe motor controller as the rate of change of position. The controllercalculates a position trajectory that dictates where the motor must beat a given time and the difference between the actual position and thedesired position is used as feedback for the motor controller. The motorcontroller then modulates the percentage of the on time of the PWMsignal sent to the one-half 918 bridge circuit to minimize the error. Aseparate quadrature counter 917 is independently read by the ControllerCPU to ensure that the Motor Controller is correctly controlling thevelocity of the motor. This is achieved by differentiating the change inposition of the motor over time.

The monitoring CPU 914 provides a safety check that independentlymonitors each of the critical signals, including signals indicative ofblood leaks, pressures in blood circuit, weight of filtrate bag, motorcurrents, air in blood line detector and motor speed/position. Themonitoring CPU has stored in its memory safety and alarm levels forvarious operating conditions of the ultrafiltrate system. By comparingthese allowable preset levels to the real-time operating signals, themonitoring CPU can determine whether a safety alarm should be issued,and has the ability to independently stop both motors and reset themotor controller and controller CPU if necessary.

FIG. 10 shows an ultrafiltration apparatus where the osmotic pressuremeasurement is separate from the hemofilter. The apparatus forultrafiltration of the blood 197 is similar to the filter shown in FIGS.3 and 4. The apparatus is equipped with a hemofilter of dialyzer 111. Anultrafiltrate or dialysate pump 114 removes plasma water, or pumps thedialysate across the filter membrane. Osmotic pressure measuring device191 is separate from the hemofilter 111. The pressure measuring device191 has a blood chamber 193 separated from the filtrate chamber 192 bymembrane 194. The membrane 194 is permeable to water and electrolytes,but impermeable to protein and blood cells.

Blood withdrawn from the patient (not shown) travels through thewithdrawal tubing 196 into the blood chamber 191, when the roller pump108 rotates. The chamber 191 presents little hydrostatic resistance toblood flow. During priming of the circuit, the filtrate chamber 192 isfilled with plasma water by applying a source of negative pressure tothe port 197. When the chamber 192 is filled and free of air, the port197 is closed. During treatment, blood from the patient flowscontinuously through the device 191. A differential pressure transducer195 measures the pressure difference between the blood chamber 193 andthe filtrate chamber 192 in the device 191. This pressure difference isthe osmotic pressure proportional to the concentration of protein inblood. This system is insensitive to changes in hydrostatic pressuregenerated by blood flow or gravity since it affects both chambersequally in device 191. While the embodiment shown in FIG. 10 requiresadditional equipment, the embodiment can be used continuously withoutstopping the blood flow to measure osmotic pressure. It can also be usedin applications where the filter 111 is used for hemodialysis. With theseparate chamber 191, the osmotic pressure difference generated byelectrolytes in the dialysis fluid passing through the filter 111 doesnot affect monitoring of the blood volume change.

The preferred embodiment of the invention now known to the invention hasbeen fully described here in sufficient detail such that one of ordinaryskill in the art is able to make and use the invention using no morethan routine experimentation. The embodiments disclosed herein are notall of the possible embodiments of the invention. Other embodiments ofthe invention that are within the sprite and scope of the claims arealso covered by this patent.

1. A device for continuously measuring osmotic pressure of blood flowingthrough an extracorporeal blood circuit comprising: a blood passagefurther comprising a withdrawal blood passage connectable to a bloodvessel in a patient and an infusion blood passage connectable to a bloodvessel in a patient; a filter further comprising a filtrate chamber, ablood chamber and a permeable membrane separating the filtrate chamberand blood chamber, wherein the blood chamber is in fluid communicationwith the blood passage; a pressure sensor measuring a pressuredifference between the filtrate chambers and the blood chamber, and acontroller receiving a pressure signal from the pressure sensor,determining an osmotic pressure across the permeable membrane of thefilter, and adjusting a rate of removal of fluid from blood in thefilter if the determined osmotic pressure level varies from apredetermined osmotic pressure setting.
 2. A device as in claim 1wherein the controller includes a processor and a memory storing acontrol algorithm to determine whether an osmotic pressure threshold isexceeded by the pressure signal from the pressure signal, saidcontroller reducing the controlled filtration if the pressure signalexceeds the osmotic pressure threshold.
 3. A device as in claim 2wherein the osmotic pressure threshold is a set by an operator prior totreating blood.
 4. A device as in claim 2 wherein the osmotic pressurethreshold is determined based on a sum of an osmotic pressure levelobtained during an initial phase of a treatment of the patient and apredetermined osmotic pressure difference.
 5. A device as in claim 1wherein the filter is a hemofilter.
 6. A device as in claim 1 whereinthe filter is a dialysis filter.
 7. A device as in claim 1 wherein thefilter is an ultrafiltration filter.
 8. A device as in claim 1 whereinthe pressure sensor comprises a pressure sensor in the blood passage. 9.A device as in claim 1 wherein the pressure sensor is a differentialpressure sensor outputting a pressure signal indicative of a pressuredifference between the blood chamber of the osmotic pressure device anda portion of the blood passage coupled to the blood chamber.
 10. Adevice as in claim 9 wherein the membrane in the permeable membrane ispermeable to electrolytes in blood flowing through the blood chamber.11. A method for preventing hypotension in a mammalian patient whoseblood is being withdrawn, treated in an extracorporeal blood circuit andinfused into the patient, said method comprising: a. measuring anosmotic pressure difference between the blood and a filtrate across apermeable membrane or filter in a blood treatment device in the circuit,and b. adjusting a rate of removal of the filtrate through the permeablemembrane or filter in the circuit if the osmotic pressure level variesfrom a predetermined osmotic pressure difference.
 12. The method forpreventing hypotension as in claim 11 wherein the predetermined osmoticpressure difference is a predetermined maximum osmotic pressuredifference.
 13. The method for preventing hypotension as in claim 11wherein the predetermined maximum osmotic pressure difference is a sumof an initial osmotic pressure difference determined during an initialphase of treating the blood in the circuit and a predetermined deltaosmotic pressure difference added to the determined initial osmoticpressure.
 14. The method for preventing hypotension as in claim 11wherein the predetermined delta osmotic pressure difference is selectedby an operator.
 15. The method for preventing hypotension as in claim 11wherein the predetermined delta osmotic pressure difference is a levelno greater than 20 percent greater than the determined initial osmoticpressure difference.
 16. The method for preventing hypotension as inclaim 11 further comprising discharging the filtrate to a filtrationcollection bag.
 17. The method for preventing hypotension as in claim 11wherein the osmotic pressure difference is determined across a filtermembrane of a filter used for fluid removal in the extracorporeal bloodcircuit, and the blood treatment device includes the filter.
 18. Themethod for preventing hypotension as in claim 11 wherein the permeablemembrane is part of a filter that comprises the blood treatment device.19. A method of controlling an extracorporeal blood circuit comprising:withdrawing blood from a withdrawal blood vessel in a patient into theextracorporeal circuit; filtering fluids from blood flowing through thecircuit at a controlled filtration rate; measuring an osmotic pressuredifference between blood and filtrate wherein the filtrate flows througha permeable membrane in the circuit; and reducing a flow rate of thefiltrate if the measured osmotic pressure exceeds a threshold osmoticpressure level.
 20. The method in claim 19 wherein the threshold osmoticpressure level is a predetermined maximum osmotic pressure difference.21. The method in claim 20 wherein the predetermined maximum osmoticpressure difference is a sum of an initial osmotic pressure differencedetermined during an initial phase of treating the blood in the circuitand a predetermined delta osmotic pressure difference added to thedetermined initial osmotic pressure.
 22. The method in claim 21 whereinthe predetermined delta osmotic pressure difference is a level nogreater than 20 percent greater than the determined initial osmoticpressure difference.
 23. The method in claim 19 wherein the thresholdosmotic pressure level is selected by an operator.
 24. The method inclaim 19 further comprising discharging the filtrate to a filtrationcollection bag.
 25. The method in claim 19 wherein the osmotic pressuredifference is determined across a filter membrane of a filter used forfluid removal in the extracorporeal blood circuit, and the bloodtreatment device includes the filter.
 26. The method in claim 25 furtherwherein the controlled filtration rate is determined by cyclicallystarting and stopping the filtration of fluids in accordance with a dutycycle and the filtration rate is reduced by increasing the portion ofthe duty cycle during which filtration is stopped.
 27. The method ofclaim 25 wherein the controlled filtration rate is determined bycyclically starting and stopping the filtration of fluids in accordancewith a duty cycle, and the filtration rate is reduced by increasing theportion of the duty cycle during which filtration is stopped.
 28. Themethod of claim 25 wherein the controlled filtration rate is determinedby cyclically starting and stopping the filtration of fluids inaccordance with a duty cycle, and the filtration rate is reduced byreducing the frequency of the duty cycle.
 29. A system for treatingblood from a patient comprising: an extracorporeal circuit having ablood passage including a blood withdrawal tube, a filter and aninfusion tube, said filter having filter blood passage in fluidcommunication with the withdrawal tube, a blood outlet in fluidcommunication with the infusion tube, a filter membrane in fluidcommunication with the blood passage, a filter output section on a sideof the membrane opposite to the blood passage, and a filtrate outputline in fluid communication with the filter output section; a pressuresensor coupled to said extracorporeal circuit and generating a pressuresignal indicative of an osmotic pressure difference across the filtermembrane and between blood in the blood passage and filtrate in thefilter output section; a filtrate pump coupled to the filtrate outputline and adapted to draw filtrate fluid from the filter at a controlledfiltration rate, and a filtrate pump controller regulating thecontrolled filtration rate based on the pressure signal indicative ofthe osmotic pressure across the membrane
 30. The system in claim 29wherein the filtrate pump controller includes a processor and a memorystoring a control algorithm to determine whether an osmotic pressurethreshold is exceeded by the osmotic pressure determined from thepressure signal, said controller reducing the controlled filtration ifthe osmotic pressure exceeds the osmotic pressure threshold.
 31. Thesystem in claim 29 wherein the osmotic pressure threshold is a set by anoperator prior to treating blood.
 32. The system in claim 29 wherein theosmotic pressure threshold is determined based on a sum of an osmoticpressure level obtained during an initial phase of a treatment of thepatient and a predetermined osmotic pressure difference.
 33. The systemin claim 29 wherein the filter is a hemofilter.
 34. The system as inclaim 29 wherein the treatment device is a dialysis filter.
 35. Thesystem in claim 29 wherein the treatment device is an ultrafiltrationfilter.
 36. The system in claim 29 further comprising an osmoticpressure sensing device separated from the therapeutic blood filter,wherein said pressure sensor determines an osmotic pressure in theosmotic pressure sensing device.
 37. The system in claim 29 wherein thepressure sensor comprises a pressure sensor in the blood withdrawal orreturn tube and a pressure sensor in the filtrate line.
 38. The systemin claim 29 wherein the pressure sensor is a deferential sensormeasuring difference between blood pressure and filtrate pressure.